Revised Abstract: The tremendous advances made in understanding the molecular details of cancer have so far failed to result in corresponding reductions in the mortality rates of the most common epithelial cancers. The goal of this project is to discover and apply emerging molecular genetic insights from colorectal cancer to rationally devise new strategies for blocking tumorigenesis. In work previously supported by the GI SPORE, a novel combinatorial chemopreventive strategy was developed using a combination of a potent irreversible inhibitor of epidermal growth factor receptor kinase and a low dose of the NSAID, sulindac. This combination proved to be particularly effective against intestinal tumors and was not associated with adverse side effects. The current proposal builds on this paradigm by proposing: 1) characterization of compounds and targets in mouse models, 2) mechanistic evaluation of molecular pathways, and 3) clinical evaluation of the most promising strategies.